A major continuing theoretical issue in neurobiology is the nature of the information encoded into chemical neurotransmitters. This problem has been intensified by major recent advances in cellular neurobiology in three specific areas of work: neuronal connectivity, synaptic mechanisms, and neuronal transmitters. Countless new interneuronal connections have been revealed through the use of sensitive new cellular tracing methods, revealing a far more detailed picture of the complexities and principles of brain organization. A whole range of ionic conductance mechanisms has been detailed by the application of new methods of electrophysiological analysis, particularly useful with the in vitro preparations. Many of these mechanisms were not previously recognized, and together they provide a much richer repertoire of receptor response mechanisms upon which neurotransmitters can operate. Last, the modern methods of chemical analysis have provided an ever-increasing list of new neurotransmitter molecules, which fall conveniently into three chemical categories: amino acids, monoamines, and neuropeptides. This review considers some possible underlying principles by which the rich signaling capacity of the central nervous system may be approached conceptually and experimentally.